Standard methods analogous to classical solid-phase methods for peptide synthesis could be applied to synthesize libraries of peptides and peptide-like compounds. In accordance with such methods, the carboxylate of N,.alpha.-Fmoc-protected (and side-chain protected) amino acids may be activated and then coupled to a resin-bound amino group. The Fmoc group is then removed followed by addition of the next monomer. Such an approach is not desirable due to the time and cost of preparing suitable quantities of a diverse set of protected N-substituted amino acid monomers. Adding and removing the Fmoc or other protective groups is time consuming and inefficient.
One approach to the discovery of new pharmaceutically active organic drugs (i.e., compounds with the 3-D structure needed for binding) relies primarily on X-ray crystallography of purified receptors: once the binding site is identified, organic molecules are designed to fit the available steric space and charge distribution. However, it is often difficult to obtain purified receptors, and still more difficult to crystallize the receptor so that X-ray crystallography may be applied. It is also nontrivial to devise an appropriate ligand, even after the binding site has been properly identified. Overall, it is extremely difficult to design useful pharmaceutically active compounds due to a number of factors such as the difficulty in identifying receptors, purifying and identifying the structures of compounds which bind to those receptors and thereafter synthesizing those compounds.
Another approach to the discovery of new drugs is to synthesize compounds which mimic known biologically active compounds. However, since the active moiety or active structural component of the active compound is usually unknown, the process of synthesizing new compounds relies primarily on trial and error and the synthesis and screening of each compound individually. This method is time consuming and expensive since the likelihood of success for any single compound is relatively low.
Rather than trying to determine the particular three-dimensional structure of a protein using crystallography or attempting to synthesize specific peptides which mimic a known biologically active peptide an art has developed with respect to the production of combinatorial libraries. More specifically, those attempting to isolate biologically active peptides produce extremely large numbers of different peptides at the same time within the same reaction vessel. The synthesized combinatorial library is then assayed and active molecules are isolated and analyzed. Combinatorial libraries per se are disclosed within U.S. Pat. No. 5,266,684. U.S. Pat. No. '684 relates almost completely to the synthesis of libraries wherein each of the reaction products in the library is a peptide comprised of the twenty naturally occurring amino acids.
Since pharmaceutically active compounds are often highly substituted heterocycles, the present inventors have found a need for a method to rapidly synthesize a large number of related substituted heterocyclic compounds quickly and relatively inexpensively. This approach would overcome the problem of a separate synthesis for each member of a group of candidate compounds where the structural components conferring biological activity are unknown.